An antibody derived from a cured AML patient to identify a unique epitope on CD43 (CD43s) as a novel target for acute myeloid leukemia and myelodysplastic syndrome.

Abstract

7009 Background: Immunotherapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hampered by the lack of tumor-specific targets. Methods: We took advantage of the tumor-immunotherapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) and searched the B cell repertoire of a patient with a lasting and potent graft versus AML response for AML-specific antibodies. Results: We identified a donor-derived B cell clone that produced an IgG1 antibody, AT1413, that specifically interacted with AML cell lines, with the patient’s autologous AML blasts, but not with lymphocytes or with cells from liver, colon, skin and other tissues. AT1413 recognized a unique, not previously described, sialylated epitope on CD43 (CD43s). CD43s is overexpressed on all types of AML and MDS, as illustrated by its reactivity with freshly isolated blasts of each of more than 60 randomly selected AML and MDS patients in our clinic, representing all WHO 2008 AML and MDS classes. AT1413 induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) of target cells in vitro. To investigate the effect of AT1413 in vivowe first generated mice populated with human effector cells (NK cells, CTL and myeloid cells) by injecting human hematopoietic stem cells into new born immunodeficient mice. After establishment of a human immune system in these mice we inoculated luciferase labeled AML cells via tail vein injection. Following engraftment of the tumor we dosed the mice biweekly with AT1413 or a control antibody. We observed strongly reduced numbers of AML cells in AT1413- but not in control antibody treated mice. Importantly, AT1413 treatment was tolerated well and did not affect numbers of non-malignant human myeloid cell in these mice. Conclusions: We have obtained an antibody from a cured AML patient which recognizes a unique sialylated epitope on CD43 (CD43s) that is selectively over-expressed on all WHO 2008 types of AML and MDS. This antibody was able to eliminate AML cells in vivo and therefore has high therapeutic potential.